Research Summary

Semaglutide Lowers hsCRP in Adults With ASCVD and Overweight or Obesity

Anthony Calabro, MA

Key Highlights

  • Semaglutide reduced high-sensitivity C-reactive protein (hsCRP) by a placebo-corrected 37.8% at 104 weeks.
  • Higher baseline hsCRP was associated with greater risks of major adverse cardiovascular events, cardiovascular death, and all-cause death.
  • Reductions in hsCRP emerged before substantial weight loss and occurred among semaglutide-treated participants with less than 2% weight loss.
  • Modeling suggested that reduced inflammation may have partially contributed to the cardiovascular benefit of semaglutide.

Once-weekly semaglutide significantly reduced high-sensitivity C-reactive protein (hsCRP), a biomarker of systemic inflammation, among adults with established atherosclerotic cardiovascular disease (ASCVD) and overweight or obesity but without diabetes, according to a prespecified secondary analysis of SELECT published in Circulation.

Higher baseline hsCRP was associated with greater cardiovascular risk, while greater reductions in hsCRP during treatment were associated with a lower risk of major adverse cardiovascular events (MACE).

SELECT was a phase 3, randomized, double-blind, placebo-controlled, event-driven trial conducted at 804 sites in 41 countries. The trial included 17,604 adults aged 45 years or older with a BMI of at least 27 kg/m² and established ASCVD but no diabetes. Participants received once-weekly subcutaneous semaglutide, escalated to 2.4 mg, or placebo in addition to standard care. Mean follow-up was 39.8 months.

Researchers examined associations among baseline hsCRP, changes in hsCRP and body weight, and time to first MACE, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The biomarker analyses primarily evaluated changes through week 104.

Study Findings

Baseline geometric mean hsCRP was 1.96 mg/L in the semaglutide group and 1.91 mg/L in the placebo group. At week 104, semaglutide reduced hsCRP by a placebo-corrected 37.8% (95% CI, −39.7% to −35.9%).

Among 6011 participants from selected European countries who underwent additional early laboratory testing, hsCRP decreased by 12% at week 4 and 19% at week 8; corresponding weight reductions were 1.4% and 2.8%, respectively. These changes occurred before participants completed dose escalation to semaglutide 2.4 mg.

Participants with baseline hsCRP of at least 10 mg/L had higher risks of MACE (hazard ratio [HR], 2.17; 95% CI, 1.81-2.58), cardiovascular death (HR, 3.94; 95% CI, 3.04-5.08), and all-cause death (HR, 3.40; 95% CI, 2.77-4.14) than those with hsCRP below 2 mg/L. Semaglutide reduced MACE consistently across baseline hsCRP categories.

Among participants with less than 2% weight loss, the ratio-to-baseline hsCRP was 0.88 with semaglutide versus 1.02 with placebo. Adjustment for time-dependent hsCRP changes attenuated the semaglutide treatment effect on MACE from an HR of 0.80 to 0.86, suggesting that hsCRP changes marked part, but not all, of the observed benefit.

Clinical Implications

According to the study authors, hsCRP measurement may help identify residual cardiovascular risk among patients with ASCVD and overweight or obesity. The findings also suggest that reduced inflammation may partially contribute to semaglutide-associated MACE reduction.

Limitations included reliance on hsCRP as a single inflammatory biomarker, no specific adjustment for multiplicity, and the potential influence of multiple factors on hsCRP. SELECT was not designed as a weight-loss intervention trial, which may have limited changes in hsCRP.

Expert Commentary

“Semaglutide use and its accompanying body weight loss were associated with decreases in hsCRP levels and MACE, suggesting a reduction in inflammation as a potential contributor to the benefits of semaglutide seen in SELECT,” the researchers concluded.

Reference
Plutzky J, Bogdański P, Colhoun HM, et al. Effect of semaglutide on the inflammatory biomarker high-sensitivity CRP in patients with established cardiovascular disease and overweight or obesity in SELECT: a prespecified secondary analysis. Circulation. Vol 154, no. 11. doi:10.1161/CIRCULATIONAHA.125.074482